Ayse AYHAN (DINÇTURK-OGAWA), currently working at Seirei Mikatahara Hospital, Hamamatsu, Japan (2004- ) as Consultant Pathologist, and Guest Professor (客員教授) of Hamamatsu and Hiroshima Universities Faculties of Medicine, Japan (from 2014) graduated from Hacettepe Univ.Sch. Medicine of Turkey in 1978, completed residency (1982) and MS on tumor biology (1990), and Ph.D. on molecular pathology at Hiroshima Univ Med. Japan. I swore Hippocratic oath to pledge myself to dedicate my life to the service of humanity.
Neoadjuvant chemotherapy in gynecological cancers is an approach that is shown to have positive e... more Neoadjuvant chemotherapy in gynecological cancers is an approach that is shown to have positive effects on survival. It increases the rate of resectability in ovarian and cervical cancers and thus contributes to survival. However, there are studies reporting that despite increasing operability, the approach does not make any changes in terms of survival. Nevertheless, no negative effects have been reported in studies conducted till today. Prospective and randomized well-designed studies that encompass a high number of cases and parameters, including cost-effectiveness, are needed in both types of cancers. Until the results of such studies are obtained, neoadjuvant chemotherapy may be taken into consideration as an alternative when conventional methods do not suffice. The number of studies concerning endometrial, vulvar and vaginal cancers are few in the area of neoadjuvant chemotherapy.
Objective: The aim of this study was to investigate the peritoneal fluid and serum lactate dehydr... more Objective: The aim of this study was to investigate the peritoneal fluid and serum lactate dehydrogenase (LDH) levels in patients with ovarian masses. Materials & methods: Peritoneal fluid and serum lactate dehydrogenase (LDH) levels were measured in 27 patients with epithelial ovarian carcinoma and 38 with benign ovarian tumors. Serum and peritoneal fluid LDH levels were also compared with the levels of CA-125. Results: Both of the marker levels in ovarian cancer patients were significantly higher than those in patients with benign ovarian tumors. Serous and undifferantiated carcinomas presented higher marker levels than endometrioid and mucinous carcinomas. High grade, advanced stage and positive cytology were associated with higher serum and peritoneal fluid LDH levels; there was an inefficient correlation between them but, when these two markers were used together with CA-125, sensitivity of CA-125 increased to 70%. Conclusions: In conclusion, serum LDH can be used to discriminate adnexal mass origin and peritoneal fluid LDH may have prognostic value because of the strict relationship with advanced stage, poor histologic type, higher grade and positive abdominal cytology. Peritoneal LDH is found to be a reliable biochemical marker related to prognosis in ovarian carcinoma patients.
BACKGROUND: Spleen tyrosine kinase (SYK) has emerged as a cancer associated kinase of which aberr... more BACKGROUND: Spleen tyrosine kinase (SYK) has emerged as a cancer associated kinase of which aberrant activity contributes to tumor development and drug resistance in several types of human cancer including ovarian carcinoma. To better understand the mechanism how the SYK pathway participates in tumor progression, we studied the biochemistry and transcriptional regulation of SYK in high-grade ovarian serous carcinoma. METHODS: Immunohistochemical analyses were performed for phosphorylated SYK (Y525/526) and total SYK levels in 42 primary serous ovarian carcinomas and 112 tumor ascites formalin-fixed paraffin embedded tissues. The relative expression of SYK long and short isoforms in peritoneal ascites and cell lines were examined by reverse transcriptase-PCR. Transcriptome analysis of gene regulated by SYK inhibition was carried out using Illumina Human HT-12 v4 arrays. Results from array was analyzed for upstream regulators. IHC data was correlated with pEGFR (Y1197) and pERBB2 (Y877) nuclear expression. Association with survival was determined by Kaplan-Meier analysis and the log-rank test. RESULTS: We observed that active phosphorylated SYK (p-SYK, Y525/526) is mainly localized in the nucleus and cytoskeleton in cell lines and tissues. Investigation of SYK mRNA spliced variants in ascites tumors showed predominant SYK long isoform expression, consistent with its nuclear localization. Survival analyses revealed that intense nuclear p-SYK correlated with poor overall survival in two ovarian carcinoma cohorts. Patients with relatively high p-SYK in the nucleus had approximately half the median survival compared to those with undetectable or low nuclear p-SYK. SYK inhibition affected changes in gene expression that are downstream of ERBB2 and EGFR signaling. Correlation analyses in tissues suggested a relationship between p-SYK and pERBB2 or pEGFR signaling. CONCLUSIONS: Our results suggest that activation of the SYK pathway leads to its phosphorylation and localization in cell nucleus. SYK activity plays a role in regulating EGFR and ERBB2 phosphorylation and activation. Thus, SYK may regulate tumor-promoting gene transcription through cross-talks with the EGFR/ERBB2 pathways. Citation Format: Yu, Yu; Ardighieri, Laura; Suryo Rahmanto, Yohan; Chen, Lin Y.; Tessarollo, Nayara G.; Mizushima, Taichi; Ayhan, Ayse; Davidson, Ben; Wang, Tian L., and Shih Ie M. ASSOCIATION BETWEEN NUCLEAR SYK PHOSPHORYLATION AND EGFR/ERBB2 PATHWAY AND POOR SURVIVAL IN HIGH GRADE SEROUS OVARIAN CANCER [abstract]. In: Proceedings of the 11th Biennial Ovarian Cancer Research Symposium; Sep 12-13, 2016; Seattle, WA. Philadelphia (PA): AACR; Clin Cancer Res 2017;23(11 Suppl):Abstract nr NTOC-115.
Background: Cancer recurrence and chemoresistance contribute greatly to the high mortality of ova... more Background: Cancer recurrence and chemoresistance contribute greatly to the high mortality of ovarian cancers; however, molecular players involved in these processes remain under-determined. Several theories have been proposed to account for the development of resistance to chemotherapeutic agents. One of the emerging concepts is tumor heterogeneity, which argues for the presence of different cell subpopulations in bulk tumor with varying degrees of tumor initiating potential and drug sensitivity. The fractions of cells with enhanced tumor initiating potential are referred to as cancer stem-like cells (CSC). These cells have defining “stemness” phenotypes, including unlimited cell division, repopulation by a minimum cell number and resistance to cytotoxic agents and irradiation. New Findings: To identify embryonic stem cell factors that are potentially involved in tumor recurrence and chemoresistance, we have screened expression levels of four of these factors by immunohistochemistry in pairs of matched recurrent and primary tumor tissues from 41 patients. Our data demonstrated that PBX1 is significantly up-regulated in recurrent/chemoresistant ovarian tumors. Moreover, PBX1 overexpression in ascites tumors correlates with shorter overall survival in post-chemotherapy ovarian cancer patients. When PBX1 is ectopically expressed, it promotes cancer stem cell-like phenotypes, including increased side population and ALDH1 activity, enhanced tumorigenicity at low cell density, and increased resistance to platinum-based therapy. In platinum-resistant cell lines that overexpress PBX1, silencing PBX1 expression using RNA interference sensitizes cells to platinum treatment and reduces their stem cell-like phenotypes. Gene expression and chromatin immunoprecipitation analyses identified PBX1 direct target genes involved in multi-drug resistance, stem cell maintenance, immunomodulation, and DNA damage response. In the TCGA ovarian cancer recurrent series, expression of several PBX1 direct target genes, including ABCA1, Nanog, BMP3, and ATM, is tightly associated with PBX1 expression, further supporting the tissue-level transcriptional regulation of these genes by PBX1. Conclusion: The above findings establish PBX1 as an upstream regulator of key functional networks that mediate cancer stem-like and drug resistant phenotypes. Studies on the hematopoietic system have indicated that PBX1 maintains a viable pool of quiescent stem cells. Recently, in a renal cell carcinoma system, chemotherapy has been shown to induce damage signaling and to stimulate cell division and repopulation of quiescent CSCs. We speculate that chemotherapy in ovarian cancer may induce comparable injury responses and trigger PBX1 signaling, which in turn may activate downstream networks that support CSC survival and create a microenvironment niche that is essential for CSC repopulation at the tissue level. Collectively, the association between PBX1 and a cascade of stemness pathways points to a potential Achilles's heel critical to responding to chemotherapy and developing chemoresistance and argues for the development of antagonists of PBX1 signaling as anticancer agents. Citation Format: Jin-Gyoung Jung, Tae-Hoen Kim, Emily Gerry, Jen-Chun Kuan, Ayse Ayhan, Ben Davidson, Ie-Ming Shih, Tian-Li Wang. PBX1, a transcriptional regulator, promotes stemness and chemoresistance in ovarian cancer. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Ovarian Cancer Research: Exploiting Vulnerabilities; Oct 17-20, 2015; Orlando, FL. Philadelphia (PA): AACR; Clin Cancer Res 2016;22(2 Suppl):Abstract nr A32.
Australian & New Zealand Journal of Obstetrics & Gynaecology, Aug 1, 1989
EDITORIAL COMMENT: This paper provides readers with a logical plan of treatment for patients pres... more EDITORIAL COMMENT: This paper provides readers with a logical plan of treatment for patients presenting with pruritus, vulvitis or visible vulvar disease who are found on directed biopsy to have vulvar dystrophy (hyperplasia, lichen sclerosus or mixed dystrophy). Excellent results were obtained using topical corticosteroid therapy for patients with hyperplasia, and topical testosterone for those with lichen sclerosus. In presenting the results in this series of 86 patients the authors do not explain the criteria for directed vulvar biopsy in women presenting with pruritus or vulvitis. These excellent results suggest that vulvar biopsy should be performed not only in all patients with clinical suspicion of carcinoma, but also in all those who fail to respond to initial therapy. The results presented here seem almost too good to believe because in this reviewer's experience vulvar biopsies in many patients with intractable pruritus and vulvitis show coexistence of hyperplasia and lichen sclerosus — in this series only 7 of 86 patients had mixed dystrophy. Readers should note that medical treatment was not used in patients with atypia on biopsy — these patients require a surgical approach to their treatment.Summary: Of 86 patients diagnosed as having vulvar dystrophy in a 10‐year period 56 (65.1%) had hyperplastic dystrophy, 23 (26.7%) had lichen sclerosus and 7 (26.7%) had mixed vulvar dystrophy. The diagnoses were made by colposcopic or toluidine blue directed biopsies. Fluorinated corticosteroids were given to patients with hyperplastic dystrophy with a response rate of 90.1%. Patients with lichen sclerosus received topical testosterone propionate and the response rate was 87.7%. Topical fluorinated corticosteroids followed by testosterone propionate was given to patients with mixed dystrophy and 85.8% of the patients responded. Surgical therapy was reserved for patients with failed medical treatment.
Neoadjuvant chemotherapy in gynecological cancers is an approach that is shown to have positive e... more Neoadjuvant chemotherapy in gynecological cancers is an approach that is shown to have positive effects on survival. It increases the rate of resectability in ovarian and cervical cancers and thus contributes to survival. However, there are studies reporting that despite increasing operability, the approach does not make any changes in terms of survival. Nevertheless, no negative effects have been reported in studies conducted till today. Prospective and randomized well-designed studies that encompass a high number of cases and parameters, including cost-effectiveness, are needed in both types of cancers. Until the results of such studies are obtained, neoadjuvant chemotherapy may be taken into consideration as an alternative when conventional methods do not suffice. The number of studies concerning endometrial, vulvar and vaginal cancers are few in the area of neoadjuvant chemotherapy.
Objective: The aim of this study was to investigate the peritoneal fluid and serum lactate dehydr... more Objective: The aim of this study was to investigate the peritoneal fluid and serum lactate dehydrogenase (LDH) levels in patients with ovarian masses. Materials & methods: Peritoneal fluid and serum lactate dehydrogenase (LDH) levels were measured in 27 patients with epithelial ovarian carcinoma and 38 with benign ovarian tumors. Serum and peritoneal fluid LDH levels were also compared with the levels of CA-125. Results: Both of the marker levels in ovarian cancer patients were significantly higher than those in patients with benign ovarian tumors. Serous and undifferantiated carcinomas presented higher marker levels than endometrioid and mucinous carcinomas. High grade, advanced stage and positive cytology were associated with higher serum and peritoneal fluid LDH levels; there was an inefficient correlation between them but, when these two markers were used together with CA-125, sensitivity of CA-125 increased to 70%. Conclusions: In conclusion, serum LDH can be used to discriminate adnexal mass origin and peritoneal fluid LDH may have prognostic value because of the strict relationship with advanced stage, poor histologic type, higher grade and positive abdominal cytology. Peritoneal LDH is found to be a reliable biochemical marker related to prognosis in ovarian carcinoma patients.
BACKGROUND: Spleen tyrosine kinase (SYK) has emerged as a cancer associated kinase of which aberr... more BACKGROUND: Spleen tyrosine kinase (SYK) has emerged as a cancer associated kinase of which aberrant activity contributes to tumor development and drug resistance in several types of human cancer including ovarian carcinoma. To better understand the mechanism how the SYK pathway participates in tumor progression, we studied the biochemistry and transcriptional regulation of SYK in high-grade ovarian serous carcinoma. METHODS: Immunohistochemical analyses were performed for phosphorylated SYK (Y525/526) and total SYK levels in 42 primary serous ovarian carcinomas and 112 tumor ascites formalin-fixed paraffin embedded tissues. The relative expression of SYK long and short isoforms in peritoneal ascites and cell lines were examined by reverse transcriptase-PCR. Transcriptome analysis of gene regulated by SYK inhibition was carried out using Illumina Human HT-12 v4 arrays. Results from array was analyzed for upstream regulators. IHC data was correlated with pEGFR (Y1197) and pERBB2 (Y877) nuclear expression. Association with survival was determined by Kaplan-Meier analysis and the log-rank test. RESULTS: We observed that active phosphorylated SYK (p-SYK, Y525/526) is mainly localized in the nucleus and cytoskeleton in cell lines and tissues. Investigation of SYK mRNA spliced variants in ascites tumors showed predominant SYK long isoform expression, consistent with its nuclear localization. Survival analyses revealed that intense nuclear p-SYK correlated with poor overall survival in two ovarian carcinoma cohorts. Patients with relatively high p-SYK in the nucleus had approximately half the median survival compared to those with undetectable or low nuclear p-SYK. SYK inhibition affected changes in gene expression that are downstream of ERBB2 and EGFR signaling. Correlation analyses in tissues suggested a relationship between p-SYK and pERBB2 or pEGFR signaling. CONCLUSIONS: Our results suggest that activation of the SYK pathway leads to its phosphorylation and localization in cell nucleus. SYK activity plays a role in regulating EGFR and ERBB2 phosphorylation and activation. Thus, SYK may regulate tumor-promoting gene transcription through cross-talks with the EGFR/ERBB2 pathways. Citation Format: Yu, Yu; Ardighieri, Laura; Suryo Rahmanto, Yohan; Chen, Lin Y.; Tessarollo, Nayara G.; Mizushima, Taichi; Ayhan, Ayse; Davidson, Ben; Wang, Tian L., and Shih Ie M. ASSOCIATION BETWEEN NUCLEAR SYK PHOSPHORYLATION AND EGFR/ERBB2 PATHWAY AND POOR SURVIVAL IN HIGH GRADE SEROUS OVARIAN CANCER [abstract]. In: Proceedings of the 11th Biennial Ovarian Cancer Research Symposium; Sep 12-13, 2016; Seattle, WA. Philadelphia (PA): AACR; Clin Cancer Res 2017;23(11 Suppl):Abstract nr NTOC-115.
Background: Cancer recurrence and chemoresistance contribute greatly to the high mortality of ova... more Background: Cancer recurrence and chemoresistance contribute greatly to the high mortality of ovarian cancers; however, molecular players involved in these processes remain under-determined. Several theories have been proposed to account for the development of resistance to chemotherapeutic agents. One of the emerging concepts is tumor heterogeneity, which argues for the presence of different cell subpopulations in bulk tumor with varying degrees of tumor initiating potential and drug sensitivity. The fractions of cells with enhanced tumor initiating potential are referred to as cancer stem-like cells (CSC). These cells have defining “stemness” phenotypes, including unlimited cell division, repopulation by a minimum cell number and resistance to cytotoxic agents and irradiation. New Findings: To identify embryonic stem cell factors that are potentially involved in tumor recurrence and chemoresistance, we have screened expression levels of four of these factors by immunohistochemistry in pairs of matched recurrent and primary tumor tissues from 41 patients. Our data demonstrated that PBX1 is significantly up-regulated in recurrent/chemoresistant ovarian tumors. Moreover, PBX1 overexpression in ascites tumors correlates with shorter overall survival in post-chemotherapy ovarian cancer patients. When PBX1 is ectopically expressed, it promotes cancer stem cell-like phenotypes, including increased side population and ALDH1 activity, enhanced tumorigenicity at low cell density, and increased resistance to platinum-based therapy. In platinum-resistant cell lines that overexpress PBX1, silencing PBX1 expression using RNA interference sensitizes cells to platinum treatment and reduces their stem cell-like phenotypes. Gene expression and chromatin immunoprecipitation analyses identified PBX1 direct target genes involved in multi-drug resistance, stem cell maintenance, immunomodulation, and DNA damage response. In the TCGA ovarian cancer recurrent series, expression of several PBX1 direct target genes, including ABCA1, Nanog, BMP3, and ATM, is tightly associated with PBX1 expression, further supporting the tissue-level transcriptional regulation of these genes by PBX1. Conclusion: The above findings establish PBX1 as an upstream regulator of key functional networks that mediate cancer stem-like and drug resistant phenotypes. Studies on the hematopoietic system have indicated that PBX1 maintains a viable pool of quiescent stem cells. Recently, in a renal cell carcinoma system, chemotherapy has been shown to induce damage signaling and to stimulate cell division and repopulation of quiescent CSCs. We speculate that chemotherapy in ovarian cancer may induce comparable injury responses and trigger PBX1 signaling, which in turn may activate downstream networks that support CSC survival and create a microenvironment niche that is essential for CSC repopulation at the tissue level. Collectively, the association between PBX1 and a cascade of stemness pathways points to a potential Achilles's heel critical to responding to chemotherapy and developing chemoresistance and argues for the development of antagonists of PBX1 signaling as anticancer agents. Citation Format: Jin-Gyoung Jung, Tae-Hoen Kim, Emily Gerry, Jen-Chun Kuan, Ayse Ayhan, Ben Davidson, Ie-Ming Shih, Tian-Li Wang. PBX1, a transcriptional regulator, promotes stemness and chemoresistance in ovarian cancer. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Ovarian Cancer Research: Exploiting Vulnerabilities; Oct 17-20, 2015; Orlando, FL. Philadelphia (PA): AACR; Clin Cancer Res 2016;22(2 Suppl):Abstract nr A32.
Australian & New Zealand Journal of Obstetrics & Gynaecology, Aug 1, 1989
EDITORIAL COMMENT: This paper provides readers with a logical plan of treatment for patients pres... more EDITORIAL COMMENT: This paper provides readers with a logical plan of treatment for patients presenting with pruritus, vulvitis or visible vulvar disease who are found on directed biopsy to have vulvar dystrophy (hyperplasia, lichen sclerosus or mixed dystrophy). Excellent results were obtained using topical corticosteroid therapy for patients with hyperplasia, and topical testosterone for those with lichen sclerosus. In presenting the results in this series of 86 patients the authors do not explain the criteria for directed vulvar biopsy in women presenting with pruritus or vulvitis. These excellent results suggest that vulvar biopsy should be performed not only in all patients with clinical suspicion of carcinoma, but also in all those who fail to respond to initial therapy. The results presented here seem almost too good to believe because in this reviewer's experience vulvar biopsies in many patients with intractable pruritus and vulvitis show coexistence of hyperplasia and lichen sclerosus — in this series only 7 of 86 patients had mixed dystrophy. Readers should note that medical treatment was not used in patients with atypia on biopsy — these patients require a surgical approach to their treatment.Summary: Of 86 patients diagnosed as having vulvar dystrophy in a 10‐year period 56 (65.1%) had hyperplastic dystrophy, 23 (26.7%) had lichen sclerosus and 7 (26.7%) had mixed vulvar dystrophy. The diagnoses were made by colposcopic or toluidine blue directed biopsies. Fluorinated corticosteroids were given to patients with hyperplastic dystrophy with a response rate of 90.1%. Patients with lichen sclerosus received topical testosterone propionate and the response rate was 87.7%. Topical fluorinated corticosteroids followed by testosterone propionate was given to patients with mixed dystrophy and 85.8% of the patients responded. Surgical therapy was reserved for patients with failed medical treatment.
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Papers by Ayse Ayhan